Mus musculus
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR040620_1.fastq.gz | Fastqsanger.gz | |||
| DRR040620_2.fastq.gz | Fastqsanger.gz | |||
| DRR040621_1.fastq.gz | Fastqsanger.gz | |||
| DRR040621_2.fastq.gz | Fastqsanger.gz | |||
| DRR040622_1.fastq.gz | Fastqsanger.gz |
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Project description:Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. ChIP-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2 binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Gene expression in BMDMs obtained from wild-type and Keap1-CKO mice. In Keap1-CKO (Keap1 flox/flox::LysM-Cre) BMDMs, Nrf2 transcription factor is activated due to Keap1-deficiency. BMDMs were obtained by a culture of bone marrow cells in the presence of M-CSF for7 days. M1-activated BMDMs were obtained by stimulation with LPS and IFNg for 6 hours, while M2-activated BMDMs were obtained by a stimulation with IL-4 for 6 hours. Two independent BMDM cultures were performed, and each experiment contains samples obtained from one wild-type and one Keap1-CKO mice, respectively.
2016-05-12 | E-GEOD-71263 | biostudies-arrayexpress
Project description:Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. ChIP-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2 binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach.
2016-05-12 | GSE71263 | GEO
Project description:In this paper we investigate one of the lesser studied TRIM family proteins, TRIM16, to determine if it might impact the ability of different viruses to replicate productively in host cells. TRIM16 is unique compared to other TRIM proteins in that it mediates E3 ligase activity despite lacking the catalytic RING domain present in other TRIM proteins. TRIM16 has been shown to play a role in innate immunity by increasing the secretion proinflammatory cytokine Il-1 in macrophages through interactions with components of the inflammasome complex (procaspase-1 and NALP-1). TRIM16 also mediates ubiquitination and aggregation of misfolded proteins which are subsequently degraded through the autophagic pathway in cells under proteotoxic and oxidative stress11. It does so through interactions with the p62-KEAP-NRF2 complex and stabilization of the NRF2 protein through multiple mechanisms11. Interestingly the NRF2 protein has been implicated in antiviral immunity, as previous studies have shown that infection of NRF2 (-/-) mice with respiratory syncytial virus (RSV) resulted in significantly higher viral titres in the lungs compared to NRF2 (+/+) mice. In addition to these clues in the literature, a recent study from our group examining transcriptional signatures in type II airway epithelial cells (AEC II) isolated from mock versus IAV-infected mice indicated that TRIM16 was upregulated in AECII following IAV infection in vivo.
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Project description:Zbtb44-mediated transcriptional repression critically regulates colonic inflammation
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Project description:Zbtb44-mediated transcriptional repression critically regulates colonic inflammation
| PRJNA1466409 | ENA
Project description:Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
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Project description:Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2’s cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/ p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/ p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.
2025-03-31 | GSE292969 | GEO
Project description:Immune checkpoint inhibitor (ICI) therapies revitalize anti-cancer responses by intercepting protein-protein interactions between exhausted CD8 T (Tex) cells and cancer cells (e.g. PD-1:PD-L1). However, up to 50% of patients receiving ICIs relapse, warranting further interrogation of the underpinnings of Tex. We conducted RNA-seq meta-analysis of Tex versus effector (Teff) mouse CD8 T cells, and highlighted NRF2 transcriptional targets as the most upregulated gene set in Tex cells. LCMV or cancer inoculation of mice bearing NRF2 hyperactive—or Keap1-/- (NRF2 negative regulator)—T cells demonstrated that NRF2 drives Tex; evidenced by increased co-inhibitory marker (PD-1/TIM-3) expression and reduced cytokine (IFN-g/Granzyme-B) production. RNA-seq of Keap1-/- highlight Ptgir—which encodes the prostacyclin lipid receptor— as the most upregulated gene versus WT T cells. Accordingly, PTGIR knockout in NRF2-hyperactive/ Tex cells decreased PD-1/TIM-3 expression, increased cytokine production, and attenuated tumor growth. Our data underscore PTGIR as a NRF2-regulated Tex driver and illuminate an unconventional immune checkpoint class potentially based on protein-lipid interactions
2025-04-25 | PXD052688 | Pride
Project description:The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), is directly involved and required for the acute activation of the inflammatory gene program. Here we show that the major transactivating subunit of NF?B, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high occupancy sites within super-enhancers. Based on these data we have developed models that with high accuracy predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell type-specific manner. Our results propose a novel paradigm for NF?B-mediated repression, whereby NF?B selectively redistributes cofactors from high occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes. Genome-wide assesment of the acute transcriptional response to TNF in human SGBS adipocytes using RNA- ChIP- and DHS-seq. Total RNA-seq and RNAPII-ChIP seq for vehicle and TNF treated adipocytes are available under GSE60462
2015-06-17 | E-GEOD-64233 | biostudies-arrayexpress